The overall goal of this U54 application is to create and support a highly multidisciplinary team of expert oncologists, biologists, biochemists, engineers and both theoretical and experimental physicists. This team will form a Physical Science-Oncology Center (PS-OC) at the Massachusetts Institute of Technology for Single-Cell Dynamics in Cancer (SCDC). The overarching goal of this team is to use both theoretical and experimental approaches inspired by Physics and Engineering to attack important problems in cancer biology by developing novel technology and analytical/computational methods to track the dynamics of cancer at the single cell level. Most investigators from our team are affiliated with institutes in the Boston area including MIT, the Whitehead Institute for Biomedical Research, the Broad Institute of MIT and Harvard, Harvard Medical School, Brigham and Women's Hospital, and Boston University. Institutions from several other investigators are located at the West coast including the University of California, San Francisco and Stanford University. One of team members is located at the Hubrecht Institute and University Medical Center Utrecht in the Netherlands. The SCDC PS-OC will be based on close collaborations between investigators originating from three fields: cancer biology, experimental physics/engineering and theoretical/computational physics. In Project 1 single-cell transcript counting will be use to develop quantitative models of stem cell differentiation and reprogramming in healthy tissue and cancer. Project 2 utilizes complementary in silico, in vitro, and in vivo studies to deconvolute Ras signaling networks in T cell lymphoma. Project 3 will explore the coordination of cell growth and division in normal and cancer cells and Project 4 focuses on characterizing the load of driver and passenger mutations in cancer by modeling neoplastic progression and analyzing genomic data. All projects will make extensive of the Single-Cell Transcript Counting Core and the Cell Sorting and Physical Measurement Core. These facilities and all reagents generated by the cores will be made available to other PS-OCs.